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An evolutionary role for HIV latency in enhancing viral transmission.

TitleAn evolutionary role for HIV latency in enhancing viral transmission.
Publication TypeJournal Article
Year of Publication2015
AuthorsIM Rouzine, Weinberger, AD, Weinberger, LS
JournalCell
Volume160
Issue5
Pagination1002-12
Date Published2015 Feb 26
ISSN1097-4172
KeywordsAnimals, Biological Evolution, Disease Models, Animal, HIV, HIV Infections, Humans, Macaca, Models, Biological, Simian Immunodeficiency Virus, Virus Latency
Abstract

HIV latency is the chief obstacle to eradicating HIV but is widely believed to be an evolutionary accident providing no lentiviral fitness advantage. However, findings of latency being "hardwired" into HIV's gene-regulatory circuitry appear inconsistent with latency being an evolutionary accident, given HIV's rapid mutation rate. Here, we propose that latency is an evolutionary "bet-hedging" strategy whose frequency has been optimized to maximize lentiviral transmission by reducing viral extinction during mucosal infections. The model quantitatively fits the available patient data, matches observations of high-frequency latency establishment in cell culture and primates, and generates two counterintuitive but testable predictions. The first prediction is that conventional CD8-depletion experiments in SIV-infected macaques increase latent cells more than viremia. The second prediction is that strains engineered to have higher replicative fitness—via reduced latency—will exhibit lower infectivity in animal-model mucosal inoculations. Therapeutically, the theory predicts treatment approaches that may substantially enhance "activate-and-kill" HIV-cure strategies.

DOI10.1016/j.cell.2015.02.017
Alternate JournalCell
PubMed ID25723173
PubMed Central IDPMC4488136
Grant ListDP1 OD017181 / OD / NIH HHS / United States
F32 AI102520 / AI / NIAID NIH HHS / United States
DP1 DE024408 / DE / NIDCR NIH HHS / United States
R21 AI109611 / AI / NIAID NIH HHS / United States
P30 AI027763 / AI / NIAID NIH HHS / United States
F32AI102520 / AI / NIAID NIH HHS / United States
U19 AI096113 / AI / NIAID NIH HHS / United States
U19AI096113 / AI / NIAID NIH HHS / United States
R21AI109611 / AI / NIAID NIH HHS / United States